Journal Article

Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1

Rojansky, Rebecca, Cha, Moon-Yong, Chan, David C

2016

Overview

A defining feature of mitochondria is their maternal mode of inheritance. However, little is understood about the cellular mechanism through which paternal mitochondria, delivered from sperm, are eliminated from early mammalian embryos. Autophagy has been implicated in nematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we show that cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination of mitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered by autophagosomes and delivered to lysosomes for degradation. The E3 ubiquitin ligases PARKIN and MUL1 play redundant roles in elimination of paternal mitochondria. The process is associated with depolarization of paternal mitochondria and additionally requires the mitochondrial outer membrane protein FIS1, the autophagy adaptor P62, and PINK1 kinase. Our results indicate that strict maternal transmission of mitochondria relies on mitophagy and uncover a collaboration between MUL1 and PARKIN in this process. Mitochondria are commonly referred to as the 'powerhouses' of animal cells because these structures provide the majority of the energy in most cells. People inherit their mitochondria from their mother, and not their father. This is because the father's mitochondria, which are delivered by sperm to the egg, are degraded early on when the embryo starts to develop. Previous studies with model organisms, like nematode worms, showed that mitochondria delivered via sperm (also known as 'paternal mitochondria') were delivered to structures called lysosomes and broken down by the enzymes contained within. However, it remained controversial whether this process, named mitophagy, also occurred in mammalian cells, and the molecules involved were unknown. Now, Rojansky et al. have identified key molecules that are essential for the degradation of mitochondria in mouse cells and show that these same molecules are needed to degrade paternal mitochondria in early mouse embryos. These results indicate that paternal mitochondria are indeed degraded by mitophagy in mice. In addition, Rojansky et al. also note that one of the key molecules is a protein called PARKIN, which is mutated in many inherited cases of Parkinson's disease, a major neurodegenerative disorder. Even though these new findings provide a clearer idea as to how paternal mitochondria are degraded, the question of why remains unanswered. As a result, it is likely that this topic will continue to be heavily debated. Nevertheless, having identified the key molecules involved in degrading paternal mitochondria, it may now be possible to address this question more directly – for example by interfering with this process and then examining the consequences.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Autophagy / Cancer Biology / Cell division / Cloning / Depolarization / DNA sequencing / Embryo, Mammalian / Embryonic development / Fibroblasts / Genes / Genetic aspects / Glucose / Haplotypes / Humans / Lysosomes / Males / Membrane proteins / Methods / Mice / Mitochondria / Mitochondria - genetics / Mitochondrial Degradation - genetics / Mitochondrial DNA / Mitochondrial Proteins - genetics / mitophagy / Nucleotide sequencing / Parkin protein / Paternal Inheritance - genetics / Phagocytosis / Phagosomes / Physiological aspects / Plasmids / Protein Kinases - genetics / PTEN-induced putative kinase / Sperm / Transcription Factors - genetics / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics